The present invention relates to polycyclic heterocyclic derivatives, to processes for their preparation and their use in human and veterinary medicine and in cosmetic compositions.
These heterocyclic derivatives find use in the topical and systemic treatment of dermatologic diseases linked to a keratinization disorder (differentiation-proliferation) and dermatologic disorders, or others, having inflammatory and/or immunoallergic components and in the treatment of conjunctive tissue degeneration illnesses. These derivatives also exhibit antitumoral activity. Moreover, these derivatives can be employed in the treatment of atrophy, be it cutaneous or respiratory and in the treatment of rheumatoid psoriasis.
Lastly, they find use in the ophthalmologic field, principally in the treatment of corneopathies.
The polycyclic heterocyclic derivatives in accordance with the present invention can be represented by the formula ##STR5## wherein
n is 1 or 2, R.sub.1 represents (i) lower alkyl, (ii) --CH.sub.2 OH or (iii) ##STR6##
R.sub.2 represents (a) hydrogen, (b) ##STR7## or (c) --OR.sub.3 wherein R.sub.3 represents hydrogen, alkyl having 1-20 carbon atoms, mono or polyhydroxyalkyl, aryl or aralkyl optionally substituted or the residue of a sugar or ##STR8## wherein p is 1, 2 or 3,
r' and r" represent hydrogen, lower alkyl, monohydroxyalkyl, polyhydroxyalkyl, aryl optionally substituted, amino acid residue, aminated sugar residue or, taken together, form a heterocycle,
X represents oxygen, sulfur, SO, SO.sub.2 or --NR.sub.4,
Y represents CR.sub.4 or a nitrogen atom, and
R.sub.4 represents hydrogen or lower alkyl, and the salts of said polycyclic heterocyclic derivatives of formula I.
By alkyl having 1-20 carbon atoms is meant, principally, methyl, ethyl, propyl, 2-ethylhexyl, octyl, dodecyl, hexadecyl and octadecyl.
By lower alkyl is meant a radical having 1-4 carbon atoms and principally methyl, ethyl, isopropyl, butyl and tert.butyl.
By monohydroxyalkyl is meant a radical having 2-4 carbon atoms and principally 2-hydroxyethyl, 2-hydroxypropyl and 2'-hydroxy-2-ethoxy ethyl.
By polyhydroxyalkyl is meant a radical containing 3-6 carbon atoms and 2-5 hydroxyl groups such as 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl, 2,3,4,5-tetrahydroxypentyl or the residue of pentaerythritol.
By residue of a sugar is meant a residue derived, for example, from glucose, mannose, erythrose or galactose.
Representative aminated sugar residues include those derived from glucosamine, galactosamine or mannosamine.
By aryl is meant phenyl optionally substituted by halogen, hydroxy, a nitro function or lower alkyl.
Representative preferred aralkyls include, preferably, benzyl as well as phenethyl.
When r' and r" taken together form a heterocycle, the heterocycle can be piperidino, piperazino, morpholino, pyrrolidino or 4-(2'-hydroxyethyl) piperazino.
When the compounds of the present invention are provided in the form of salts they can be salts of an alkali or alkaline earth metal or even of zinc, or of an organic amine when they have at least one free acid function, or salts of a mineral or organic acid, principally, hydrochlorides, hydrobromides or citrates when they have at least one amine function.
Representative compounds of formula I include, principally, the following:
methyl ester of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphtho[2,3-b]furyl) benzoic acid, PA0 p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphtho[2,3-b]thienyl) benzoic acid, PA0 p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-1H-benz[f]indolyl) benzoic acid, PA0 methyl ester of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-1H-benz[f]indolyl) benzoic acid, PA0 methyl ester of p-(1-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-benz[f]indolyl) benzoic acid, PA0 p-(1-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-benz[f]indolyl) benzoic acid, PA0 methyl ester of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzoic acid, PA0 p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzoic acid, PA0 p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzyl alcohol, PA0 p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzoic aldehyde, PA0 ethylamide of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzoic PA0 morpholide of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzoic acid, PA0 2-hydroxyethyl ester of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzoic acid, PA0 methyl ester of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]imidazolyl) benzoic acid, PA0 p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]imidazolyl) benzoic acid and PA0 2-(4-methyl)phenyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphth[2,3-d]imid azole. PA0 p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphtho[2,3-b]thienyl) benzoic acid and its methyl ester, PA0 p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-1H-benz[f]indolyl) benzoic acid and its methyl ester, PA0 p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzoic acid and its methyl ester, PA0 p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]imidazolyl)benzoic acid and its methyl ester, and PA0 p-(1-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-benz[f]indolyl) benzoic acid and its methyl ester. PA0 2,3-diamino-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl naphthalene and PA0 3-amino-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol. PA0 acne vulgaris, comedons or polymorphs, solar senile acne and medicinal or professional acne, PA0 solar keratites, PA0 extensive or severe forms of psoriasis, and other keratinization disorders and principally ichtysoses and ichtysosis like conditions, PA0 Darier malady, PA0 palmo-plantar keratodermies, PA0 leucophasies and leucophasis-like states, lichen plan, and PA0 all malignant or benign dermatologic proliferations, severe or extensive.
p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphtho[2,3-b]furyl) benzoic acid,
methyl ester of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphtho[2,3-b]thienyl) benzoic acid,
Particularly preferred compounds of formula I in accordance with the present invention are those having the following formula: ##STR9## wherein
R.sub.3 represents hydrogen or lower alkyl,
X represents oxygen, sulfur or NR.sub.4,
Y represents CR.sub.4 or a nitrogen atom, and
R.sub.4 represents hydrogen or methyl.
Representative compounds corresponding to formula II include, principally:
The present invention also relates to a process for the preparation of the compounds of formula I.
These compounds can be obtained in accordance with two synthesis methods: